Bladder cancer is a leading cause of death worldwide. Bladder cancer is more than three times more common in men than women though the mortality rate in the latter is twice as great. Most of the patients who present with superficial bladder cancer tumours will experience a recurrence within 5 years and almost 90% of these patients will have a recurrence within 15 years. As such, it is vital that these patients are followed up on a regular basis to ensure that the cancer does not spread beyond the bladder. The constant monitoring and the costly diagnostic techniques results in bladder cancer being, on a cost per patient basis, the most expensive cancer to manage from diagnosis to death.
The usefulness of a diagnostic test is measured by its sensitivity and specificity. The sensitivity of a test is the number of true positives (the number of individuals with a particular disease who test positive for the disease) and the specificity is the number of true negatives (the number of individuals without a disease who test negative for the disease). The most common sign of bladder cancer is gross or microscopic haematuria, often detected by the family physician, and is observed in 85% of all bladder cancer patients. A simple urine dip test can be used to detect the presence of blood. Although cancer without blood is rare, leading to high sensitivity of a simply blood dip test, the specificity of the test is poor with fewer than 5% of patients presenting with haematuria actually having bladder cancer. However, the 5% of patients who do present are normally diagnosed with superficial tumours, which can easily be resected.
Cystoscopy and cytology are the preferred methods used to diagnose bladder cancer. A cytological examination involves the examination of urothelial cells in voided urine. This method has high specificity and it is convenient to obtain a sample. However, it has poor sensitivity and is subjective at low cellular yield. A cytological assessment is usually combined with flexibly cystoscopy. Cystoscopy allows direct observation of the bladder and biopsy of suspicious regions and results in 95% accuracy in diagnosis. It is therefore considered the gold standard in accurately diagnosing bladder cancer.
However, there are some disadvantages associated with cystoscopy, namely that it is extremely expensive, causes patient discomfort and does not allow for upper tract visualisation or for the detection of small areas of carcinoma in situ. Attempts have been made in the art to identify one or more biochemical bladder cancer biomarkers that could identify patients who present with bladder cancer before committing them to cystoscopy. At the present time approximately 20% of patients present with advanced disease and their prognosis is poorer as a result. Attempts have therefore been made in the art to identify a proven marker or panel of markers, which could be used as a screening tool for bladder cancer for high-risk asymptomatic patients.
No single biomarker or panel of biomarkers has yet achieved the levels of sensitivity and specificity required to reduce the frequency of cystoscopy needed for an accurate diagnosis. Over the last 10 years a large number of bladder cancer markers including BTA STAT, NMP22, telomerase and FDP, have been evaluated against the gold standard urine cytology with quite consistent results of low specificity. These markers are present in urine in a large proportion of patients with urological pathologies other than bladder cancer and in patients with urinary infections. NMP22 and BTA have FDA approval as point of care assays. However, NMP22 requires immediate stabilisation in urine, which is not always possible, and the presence of BTA can be masked by blood present in the urine. New putative markers, such as survivin, hyaluronic acid, cytokeratin 8 and 18 and EGF, which have been shown to induce expression of the matrix metalloproteinase (MMP9) in some bladder cancer cells have been proposed as bladder cancer markers. However, none of the putative biomarkers have been bench-marked against the high specificity of urine cytology and the high sensitivity of the telomerase assay.
Thus, in the field of bladder cancer diagnosis and treatment, the biomarkers identified in the prior art are unsatisfactory since they lack the required sensitivity and specificity required to make an accurate diagnosis of bladder cancer or assessment of a patient's risk in developing the disease. As a result the clinician is not able to accurately assess whether a patient should be put forward for further cytoscopic and cytological tests which results in high costs associated with diagnosing and managing the disease. An aim of the present disclosure is to overcome these problems.